Conserved Roles of Sp1 in Zebrafish Development and Early Organogenesis

Transcription factors (TFs) function in combinatorial networks to orchestrate gene expression during development and disease. Yet, the mechanisms underlying their context-specific regulatory roles remain poorly understood. Here, we investigate Specificity Protein 1 (Sp1), the first sequence-specific transcription factor identified and a key regulator of TATA-less gene promoters as a model to elucidate conserved and lineage-specific functions in vertebrate development. While Sp1 is extensively studied in mammalian systems, particularly in cancer progression, its evolutionary acquisition and developmental roles in early vertebrates remain unexplored. Using zebrafish as a model, we characterized the spatiotemporal expression dynamics and functional significance of sp1 during embryogenesis. Loss-of-function analyses revealed profound morphological defects across multiple organ systems, including skeletal, neural, and gastrointestinal tissues. Complementary stage-specific transcriptomic profiling uncovered widespread dysregulation of lineage-defining genes and perturbations in core cellular pathways related to the cell cycle, DNA metabolism, and apoptosis. Together, our findings establish Sp1 as a pivotal transcriptional regulator in early vertebrate development and reveal mechanistic insights into how conserved TF networks coordinate developmental programs and context-dependent disease states. Summary statementThis study characterizes the expression profile and establishes the conserved role of SP1 in specific processes during zebrafish development, which were previously unreported.